Dataset Information

Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.

ABSTRACT: Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that ?-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with ?-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.

SUBMITTER: Heallen T

PROVIDER: S-EPMC3133743 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.

Heallen Todd T Zhang Min M Wang Jun J Bonilla-Claudio Margarita M Klysik Ela E Johnson Randy L RL Martin James F JF

Science (New York, N.Y.) 20110401 6028

Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecip ...[more]

PMID: 21512031

Similar Datasets

Project description:The Hippo signaling pathway is involved in the formation and development of the cardiovascular system. In the present study, the effects of WWC family member 3 (WWC3) on vascular smooth muscle cells (VSMCs) following injury were investigated, in addition to the associated mechanisms underlying this process. Platelet‑derived growth factor BB (PDGF‑BB) was used as a cell injury factor, and rats with balloon injuries were used as a model of carotid intimal injury. Furthermore, the expression levels of WWC3 in VSMCs and arteries post‑injury were investigated, in addition to the effect of WWC3 on the proliferation and migration of VSMCs. The results demonstrated that following injury, WWC3 expression was suppressed in VSMCs and the rat carotid artery, and the activity of the Hippo signaling pathway was significantly downregulated. In addition, the expression of YY1‑associated protein‑1 (YAP) and a number of its downstream target genes, including connective tissue growth factor (CTGF), were enhanced, thus enhancing the proliferation and migration of VSMCs. Knockdown of WWC3 suppressed the levels of large tumor suppressor kinase 1 (LATS1) expression and YAP phosphorylation, and the expression of YAP, CTGF and cyclin E was subsequently enhanced, thus promoting cell proliferation and migration. Similar results were obtained following overexpression of WWC3. Treatment with PDGF‑BB was revealed to suppress the proliferation and migration of VSMCs transfected with the WWC3 plasmid, compared with VSMCs transfected with an empty vector. The present study demonstrated that WWC3 may interact with LATS1 in order to upregulate the Hippo signaling pathway via co‑immunoprecipitation and enhancement of the phosphorylation of LATS1, in addition to the corresponding suppression of the nuclear import of YAP. However, VSMCs transfected with WWC3 plasmid with a deletion of the WW domain fail to exhibit this effect. These results suggested that WWC3 expression is downregulated in VSMCs during neointimal hyperplasia following injury (PDGF‑BB stimulation or balloon injury). WWC3 upregulates the activity of the Hippo signaling pathway, and weakens the proliferation and migration of VSMCs. Furthermore, the results of the present study suggested that WWC3 may interact with LATS1 to promote the phosphorylation of YAP and reduce its nuclear translocation, upregulate the activity of the Hippo pathway, and suppress the proliferation and migration of VSMCs following injury.

Dataset Information

Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.

Publications

Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets